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Glukokortikoide (GC) stellen die Standardtherapie in der Remissionsinduktion und -erhaltung der Riesenzellarteriitis (RZA) dar. Additive immunsuppressive Therapien werden bisher nur in bestimmten Situationen empfohlen (z. B. bei Refraktaritat, Rezidiven und GC-induzierten Nebenwirkungen). Uber viele Jahre stand Methotrexat (MTX) als klassische GC-einsparende Therapie zur Verfugung. Mittlerweile gilt Tocilizumab als Mittel der Wahl zur GC-Einsparung, welches das erste fur die Riesenzellarteriitis zugelassene Biologikum ist. Langzeitdaten uber 3 Jahre hinaus fehlen jedoch. Zurzeit werden weitere vielversprechende bDMARDs („biological disease modifying antirheumatic drug“) und tsDMARDs („targeted synthetic disease modifying antirheumatic drug“) in RCTs („randomized controlled trial“) untersucht, die moglicherweise zukunftig dazu beitragen konnen, zusatzliche effektive GC-einsparende Optionen in der Therapie der RZA zu bieten und eine additive steroideinsparende Medikation als therapeutischen Standard zu etablieren. Dieser Beitrag gibt eine Ubersicht uber aktuelle Therapiestudien der RZA.

Glucocorticoids (GC) represent the standard treatment in remission induction and maintenance in the treatment of giant cell arteritis (GCA). Additive immunosuppressants are currently only recommended in special situations, such as refractory or relapsing disease or in cases of glucocorticoid-induced side effects. Methotrexate has been the standard steroid-sparing agent for many years. Meanwhile, tocilizumab is the first choice for steroid reduction, which was the first biological to be licensed for the treatment of GCA; however, long-term data over more than 3 years are lacking. A number of promising bDMARD and tsDMARD are currently being investigated in randomized controlled trials (RCT), which could contribute to additional effective steroid-sparing options in the treatment of GCA and help to establish an additive GC-sparing medication as the standard treatment in the future. This article gives an overview on current treatment studies for GCA.

Rheumatologist should be familiar with the concept of IgG4-related disease (IgG4-RD). Due to the clinical spectrum IgG4-RD can fall directly within the scope of rheumatology and are often diagnosed primarily by rheumatologists. Furthermore, IgG4RD are relevant differential diagnoses for many other rheumatic conditions. Finally, there are an increasing amount of data suggesting an important role of immunological processes observed in IgG4-RD for other rheumatic diseases.

Neben den selteneren ANCA-assoziierten Vaskulitiden (AAV), die sich haufig mit einem pulmorenalen Syndrom und/oder pulmonalen Granulomen manifestieren, stellen die interstitielle Lungenerkrankung und der pulmonale Hypertonus haufigere Komplikationen rheumatologischer Erkrankungen, insbesondere der Kollagenosen dar. Die Bestimmung des ANCA mit Nachweis eines der charakteristischen Zielantigene, Proteinase-3 (PR3) oder Myeloperoxidase (MPO), ist diagnostisch richtungweisend fur das Vorliegen einer AAV, wahrend bei dem Verdacht auf eine Kollagenose zunachst antinukleare Antikorper (ANA) und bei positivem Befund nachfolgend eine ANA-Differenzierung vorgenommen werden sollte. Antikorper der ANA-Differenzierung sind oft hoch-spezifisch fur eine bestimmte Kollagenose (wie z. B. Topoisomerase-1-Antikorper bei der systemischen Sklerose). Der Nachweis von CCP-Antikorpern hat die Diagnostik der rheumatoiden Arthritis (RA) wesentlich bereichert. Neben ihrem prognostischen Wert hinsichtlich eines erosiven Verlaufs der RA sind sie mit extraartikularen Manifestationen assoziiert.

The vasculitides represent one group of the systemic rheumatic diseases. Among the vasculitides we distinguish between large- (i.e. giant cell arteritis), medium- (i.e. polyarteritis nodosa) and small-vessel vasculitides (i.e. ANCA-associated vasculitides). Granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis belong to the ANCA-associated vasculitides. They share the features of vasculitic manifestations in small- to medium-sized vessel beds (which can occur in almost any organ system) and the presence of ANCA, the detection of which, however, is not necessarily mandatory. The treatment of AAV depends on disease stage and activity and is carried out on the basis of randomized controlled trials with an initial regimen aimed at inducing remission followed by maintenance treatment. In addition to glucocorticoids, conventional immunosuppressants (such as methotrexate, azathioprine and cyclophosphamide) form the basis of treatment, whereby rituximab, first licensed for the treatment of severe active GPA and MPA in 2013, has emerged as new treatment option.

Granulomatosis with polyangitis (GPA, Wegener's granulomatosis) is characterized by a granulomatous inflammation of the respiratory tract and a necrotizing ANCA-associated small to medium-size vessel vasculitis with a predilection for the lungs (pulmonary capillaritis) and kidneys (necrotizing glomerulonephritis). The disease evolves stage-wise and typically starts as inflammation of the respiratory tract followed by development of systemic vasculitis manifestations. Today, treatment is evidence-based and adapted according to activity and disease stage which has resulted in a significant improvement in long-term outcome. Early mortality during the first year of treatment poses one of the main problems and is a result of infections under immunosuppressive treatment. Furthermore, treatment of refractory disease activity which is often represented by granulomatous manifestations is still a challenge and may result in significant organ damage if not treated successfully.

Neurologic complications of vasculitis occur frequently in the form of either peripheral neuropathy or manifestations within the central nervous system (CNS). Primary vasculitis of the CNS is characterized by central nervous system manifestations only with no evidence of systemic disease manifestations. Large vessel vasculitis is particularly associated with central nervous system complications, such as ischemic cerebral infarcts whereas medium size, e.g. polyarteritis nodosa and small vessel vasculitis, e.g. antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis manifest with peripheral neuropathies and central nervous system complications. The same also holds true for Behçet's disease which affects both large, medium and small sized arteries and veins. Due to the severity of nervous system manifestations a highly potent immunosuppressive therapy (e.g. cyclophosphamide and glucocorticoids) is usually required for remission induction. Virus-associated vasculitis (e.g. hepatitis C-associated cryoglobulinemic vasculitis) should receive antiviral therapy as first line treatment. Chronic damage is frequent in spite of swift initiation of immunosuppressive treatment.

Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).To test the validity and the mechanism of this association between α1AT and AAV.The distribution of α1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay.were compared between cases and controls using χ(2) tests. The serum and renal biopsies for α1AT polymers were compared using the polymer-specific 2C1 antibody. The role of α1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of α1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p0.001); polymers of α1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of α1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse.The Z but not the S deficiency allele is associated with AAV. Polymers of α1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils.

The stringent definition of disease and activity stage as well as the performance of several controlled trials in the field of vasculitis in the past years now enables an evidence-based stage and activity adapted treatment, especially for ANCA-associated vasculitides. On the basis of available controlled trials, the European League Against Rheumatism (EULAR) and European Vasculitis Study Group (EUVAS) established and published recommendations for the management of vasculitides. This manuscript summarizes the treatment recommendations published in 2009 and highlights new studies which have been published since then.

Genetic association studies have been of great value in the past by contributing to the understanding of pathophysiological mechanisms of chronic inflammatory and autoimmune diseases. Many genetic risk factors have been identified which confer susceptibility for one or several (autoimmune) disease(s). Using a candidate-gene approach, the first genetic risk factors and polymorphisms of vasculitides have been identified. Due to the rarity of autoimmune vasculitides often only small sample numbers have been generated and analysed, leading to inconsistent results. Furthermore, differences in ethnic background may complicate analysis. Only few of the detected risk factors have been reliably replicated in larger cohorts, such as the association of the PTPN22*620W allele with WG and MPA, the deficiency allele Pi*Z of the alpha1 antitrypsin gene and the HLA-DPB*04041 allele with WG and the HLA-DRB3/DRB4 with CSS. Genome-wide association studies (GWAS) offer the advantage of screening the whole genome for risk factors rather than relying on disease models postulated by the investigator; however, they require even larger sample sizes. Initial results from GWA studies are available for Behçet's disease and Kawasaki syndrome, which identified new genetic associations but require replication, especially since some of the identified risk factors could not be linked to pathophysiological pathways to date.

Vasculitis is still being classified according the criteria of the American College of Rheumatology and the Chapel Hill Consensus Conference Definitions. Diagnostic criteria are currently being established. The classification criteria are based on the size of the inflamed blood vessel (e.g. large vessel vasculitis with inflammation of the aorta and its branches), clinical symptoms and findings (such as cephalalgia in giant cell arteritis) and histological findings. In recent years a definition of disease stages and activity has been established and a number of controlled trials have been carried out in order to provide evidence-based stage and activity adapted therapy regimens. Recommendations for the management of vasculitis have been published in 2009 by EULAR (European League Against Rheumatism). This article gives a review of the classification of vasculitis and summarizes the current European guidelines on management.

Many, different diseases can result in pulmonary fibrosis and its prevalence is continuously increasing. Pulmonary fibrosis is defined by a diffuse accumulation of connective tissue in the interstitial space resulting in destruction of lung parenchyma. Older individuals are more often affected by this disease than younger. Approximately one half of all patients with pulmonary fibrosis suffer from rheumatic diseases. The classification of pulmonary fibrosis was revised 1998. Now 6 different types of interstitial pneumonia according to 6 different pathologic patterns are newly defined. Still, there is no efficient treatment known, which resolves fibrotic lung remodeling. However, immunosuppressive treatment strategies are established in pulmonary fibrosis evoked by inflammatory processes.

Recently, the European League Against Rheumatism (EULAR) published recommendations on the management of patients with primary systemic vasculitides. The use of the given definitions for different activities and stages of the diseases is encouraged not only in clinical trails but also for the purpose of harmonisation in daily routine. Concerning the diagnostic work-up an interdisciplinary approach in co-operation with expert-centre is recommended. Therapy consists of remission induction and maintenance. For induction therapy in small vessel vasculitis cyclophosphamide or medium potent immunosuppressants such as methotrexate plus glucocorticoids should be used according to disease stage and activity. Glucocorticoids also represent the mainstay of remission induction in large vessel vasculitis. Additional immunosuppressants should be considered, if the disease can not be controlled by glucocorticoids or for the purpose of sparing glucocorticoids. Refractory disease should be treated within clinical trails. Further recommendations deal with monitoring of diseases activity and therapy as well as with measures to avoid complications and late sequelae.

Proteinase 3 (PR3) is a multifunctional neutrophil-derived serine protease influencing cell cycle, differentiation, and cell death. This molecule is the main target antigen of autoantibodies in Wegener's granulomatosis (WG) known as antineutrophil cytoplasmic antibodies (PR3-ANCA). WG usually starts as granulomatous inflammation of the upper respiratory tract (localized phase) and progress to systemic disease with PR3-ANCA-associated vasculitis (generalized phase). PR3-ANCA is thought to play a critical role in the pathogenesis of vascular damage in WG. In contrast, it is not clear how the granulomatous inflammation, the hallmark of WG, is driven, and what is the relationship between granuloma and autoimmunity. Recent findings provide evidence that PR3 might function as endogenous "danger/alarm" signal that communicates the presence of tissue injury to dendritic cells (DC) via protease-activated receptor-2 (PAR-2), triggers their maturation and instructs DC to induce Th1-type cell responses in WG. Furthermore, PR3 has the capacity to bind and activate IL-32, a recently discovered proinflammatory cytokine that has emerged as an important player in innate and adaptive immune response.Collectively, these results delineate new pathogenic pathways at the molecular level and provide insights into the mechanisms by which PR3 may contribute to the early pathogenesis of WG supporting the pivotal role of the interaction of Wegener's autoantigen with the "gateway" receptor PAR-2 in mediating both innate and adaptive immune response in WG.

Tumor necrosis factor (TNF-alpha) plays an essential role in the orchestration of inflammatory processes including autoimmune disorders, host defence and granuloma formation. TNF antagonists are highly effective in the therapy of rheumatoid arthritis, but they compromise host defence mechanisms, especially concerning bacterial infections inducing granuloma formation, such as tuberculosis. Other biologics have been developed and approved for the therapy of rheumatoid arthritis, e.g. an interleukin (IL-1) blocking agent (anakinra), an antibody that depletes CD20 positive B-cells (rituximab) and an inhibitor of T-cell co-stimulation (abatacept). In spite of initial skepticism regarding side effects, such as an increased risk of infections, biologics now play an essential role in the therapy of autoimmune diseases due to the implementation of efficient screening measures concerning side effects (such as reactivation of tuberculosis). This review summarizes the current available data regarding risk of infection and gives and overview on recommended screening, contraindications and events that require withdrawal of therapy.